Methods for the In Situ Treatment of Bone Cancer

ABSTRACT

The present invention relates to methods for in situ treatment of malignant cells from a cancer associated with bone. In one method, the treatment is for a primary cancer and entails positioning an implant containing and/or coated with at least one active agent for treating malignant cells directly in/on or indirectly among/near (e.g., by placing the implant in an area immediately proximal to) a site containing the malignant cells. In another method, the treatment includes positioning an implant containing and/or coated with at least one active agent for treating malignant cells directly in/on or indirectly among/near (e.g., by placing the implant in an area immediately proximal to) a surgical site from which malignant cells were previously removed/excised.

STATEMENT OF RELATED CASES

This application claims priority to U.S. Provisional Application No.60/678,734 filed on May 6, 2005, and is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to methods for in situ treatment ofmalignant cells from a cancer associated with bone.

BACKGROUND OF THE INVENTION

Because of the tremendous impact of hyperproliferative diseases such ascancer on an ever-growing world population, there are a plethora oftreatment methods that are as varied as the many different types ofcancer. While general chemotherapeutic treating regimens can sometimesbe effective in controlling certain types of cancer, their side effectsoften render them distasteful or unendurable by patients. These generalchemotherapeutic treatment regimens typically take much the same form asother therapeutic/pharmaceutical delivery methods for severe illnesses,e.g., oral, intravenous, parenteral, etc. However, the fact that suchdelivery methods result in a widespread cellular toxicity, which is themajor cause of many undesirable side effects, is a problem withconventional chemotherapy.

This down side of conventional chemotherapeutic cancer treatments can beminimized by using delivery mechanisms that specifically target cancercells or certain hyperfunctionalities associated with malignancy, e.g.,increased blood flow, increased vascularization, increased replicativefunction/hyperproliferation, increased selective cellular transport,etc. Many publications describe specific types of compounds (drugs) thatseek out specific cells or areas having increased or decreased cellularfunctions specific to malignancies. Many other publications describemodified compounds, or prodrugs, in which an active compound is renderedtemporarily inactive and chemically attached to a moiety (or group ofmoieties) designed to seek out specific cells or areas having increasedor decreased cellular functions specific to malignancies, and designedto re-activate the compound at the desired time/location in vivo. Stillother publications describe the use of physically sequestered compounds,e.g., time-release dosage forms, degradable drug reservoirs,pH-activated gate devices, multi-reservoir implantable chips, or thelike, for treating cancer. Nevertheless, all of these methods rely onlong-distance targeting, i.e., using seeker molecules that travelthrough the body until they find their target, only then unloading theirtreatment payload.

Cancers related to the skeletal system can be difficult to treat withconventional chemotherapy. For these types of cancers, an in situtreatment mechanism is needed for releasing active agents that need notbe target-specific to avoid the widespread side effects of traditionalchemotherapy, due to an immediate in vivo proximity to the malignantcells by virtue of in situ implantation.

Implants for treating/fixing bone injuries/deformities are well known.But because bones and orthopedic implants are essentiallyintermediate-term scaffolds (often load bearing, but designed tobiodegrade slowly to allow bone to regrow around them/in their place),they have been utilized mostly for structural purposes. Further, whilethe surface characteristics of orthopedic implants have been oftenaltered, that alteration has typically been for purposes of mechanicalstability and/or biocompatibility. To the extent that there have beenprior publications on active agent-loaded implantable materials, thosepublications have largely involved soft tissue or organs, and havelargely centered on treatment of different maladies/diseases/conditions.

The present invention, as described below, offers several uniquesolutions to the problems and difficulties previously described.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a method for in situ treatment ofmalignant cells from a cancer associated with bone, which includespositioning among the malignant cells an implant that at least partiallychemically and/or physically associates with at least one active agentfor treating the malignant cells. Advantageously, in one embodiment, thecancer associated with bone is a primary cancer.

Another aspect of the invention relates to a method for in situtreatment of malignant cells from a cancer associated with bone, whichincludes positioning among the malignant cells an implant that at leastpartially chemically and/or physically associates with at least oneactive agent for treating the malignant cells. In one preferredembodiment, the implant advantageously does not include a hardened bonecement within the bulk of which the at least one active agent iscontained.

Another aspect of the invention relates to a medical device for in situtreatment of malignant cells from a cancer associated with bone, whichcontains:

a sterile, coated implant including a screw; a tack; a nail; a pin; aplate; a rod; a clamp; a staple; a spring; a stent; a suture; amembrane; a catheter; a pacemaker or other electronic device lead; axenograft, heterograft, or allograft portion of bone, soft tissue,extracellular matrix, cartilagenous material, or a combination thereof;a composition of or containing artificial bone, demineralized bonematrix, soft tissue, extracellular matrix, cartilagenous material, or acombination thereof; a bone cement; or a combination thereof,

wherein the implant at least partially chemically and/or physicallyassociates with at least one active agent including a bisphosphonate, amonophosphonate, vitamin D and/or a vitamin D derivative, calcitonin, astatin, an anti-angiogenesis agent, an anticancer agent, anantiproliferative agent, an osteoclast inhibitor, a vasodilator, or acombination thereof.

In a preferred embodiment, the implant possesses a coating layerincluding a (co)polymer that contains: aliphatic ethers; aliphaticesters; alkylene esters; aromatic esters; aliphatic amides; polyamides;siloxanes; urethanes, urethaneureas, or both, having hard segments madefrom multifunctional isocyanates in combination with multifunctionalhydroxy compounds, multifunctional amines, or both; alpha-olefins; atleast partially halogenated repeat units; ionomers; hyaluronic acidand/or a salt thereof; collagen; and combinations, copolymers, orreaction products thereof, and

Another aspect of the invention relates to a kit for in situ treatmentof malignant cells from a cancer associated with bone, which contains:

(1) a sterile, coated implant including a screw; a tack; a nail; a pin;a plate; a rod; a clamp; a staple; a spring; a stent; a suture; amembrane; a catheter; a pacemaker or other electronic device lead; axenograft, heterograft, or allograft portion of bone, soft tissue,extracellular matrix, cartilagenous material, or a combination thereof;a composition of or containing artificial bone, demineralized bonematrix, soft tissue, extracellular matrix, cartilagenous material, or acombination thereof; a bone cement; or a combination thereof, and

(2) one or more sterile solutions, carriers, or both, each solution,carrier, or combination thereof containing at least one active agentincluding a bisphosphonate, a monophosphonate, vitamin D and/or avitamin D derivative, calcitonin, a statin, an anti-angiogenesis agent,an anticancer agent, an antiproliferative agent, an osteoclastinhibitor, a vasodilator, or a combination thereof.

In one embodiment of this aspect, the implant possesses a coating layercontaining: aliphatic ethers; aliphatic esters; alkylene esters;aromatic esters; aliphatic amides; polyamides; siloxanes; urethanes,urethaneureas, or both, having hard segments made from multifunctionalisocyanates in combination with multifunctional hydroxy compounds,multifunctional amines, or both; alpha-olefins; at least partiallyhalogenated repeat units; ionomers; hyaluronic acid and/or a saltthereof; collagen; and combinations, copolymers, or reaction productsthereof.

These and other features and advantages of the present invention willbecome apparent from the remainder of the disclosure, in particular thefollowing detailed description of the preferred embodiments, all ofwhich illustrate by way of example the principles of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

One aspect of the present invention relates to a method of implanting asterile, active agent-coated material and/or device for implantationinto a subject. Advantageously, the method can include, but is notlimited to, the following steps: providing a sterile implantablematerial and/or device (hereinafter “sterile implant,” for convenienceonly and without intent to limit) that is capable of physically and/orchemically associating with an active agent; contacting the sterileimplant with an active agent, e.g., by at least partially exposing thesterile implant to a preferably sterile solution containing the activeagent, so that the sterile implant at least partially physically and/orchemically associates with the active agent, thus forming an activeagent-loaded sterile implant; and at most a relatively short time afterforming the active agent-loaded sterile implant, implanting the activeagent-loaded sterile implant into a subject, e.g., an animal such as amammal, preferably a primate or a human. For instance, see U.S. patentapplication Ser. No. 11/108,040 to M. Maccecchini, filed Apr. 15, 2005,and entitled “Method of Coating a Sterile, Active Agent-Coated Materialand Composition Made According to Same,” the entire disclosure of whichis expressly incorporated by reference herein.

Before a sterile implant can be provided, typically a non-sterileimplant is formed. This non-sterile implant may contain, or be madefrom, any suitable material, preferably a biocompatible material, andoptionally but preferably a bioabsorbale, bioresorbable, and/orbiodegradable material. Exemplary implant materials can include, but arenot limited to: natural and/or synthetic (co)polymers; metals; metalalloys; glasses (e.g., bioactive glasses such as E-glass);metal-containing compounds such as metal oxides (e.g., ceramics),hydroxides, carbonates, nitrates, phosphates, sulfates, and the like;and the like; and combinations thereof.

The natural and/or synthetic polymers can be thermoplastic or thermoset,elastic or viscoelastic, elastomeric or non-elastomeric,semi-crystalline or amorphous, oriented or unoriented, hydrogen-bonded,or non-hydrogen-bonded, and the like, depending upon the application forwhich they are to be used. Natural and/or synthetic polymers can behomopolymers, blends of homopolymers, copolymers, blends of copolymers,or blends of homopolymers and copolymers. If homopolymeric, the naturaland/or synthetic polymers can be, but are not limited to being, atactic,isotactic, syndiotactic, dendritic, long-chain branched/grafted,short-chain branched/hairy-rodlike, uncrosslinked, crosslinked,multi-armed stars, or the like, or some combination thereof. Ifcopolymeric, the natural and/or synthetic polymers can include, but arenot limited to, block copolymers (e.g., diblock or triblock), multiblockcopolymers, long- and/or short-chain graft copolymers, long- and/orshort-chain multigraft copolymers, long- and/or short-chain combcopolymers, random copolymers, alternating copolymers, hetero-armed starcopolymers, diblock armed star copolymers, triblock armed starcopolymers, multiblock armed star copolymers, and the like, andcombinations or copolymers thereof. Copolymers according to theinvention may contain two different types of repeat units or may containmore than two different types of repeat units (e.g., terpolymers containthree different types). (Co)Polymers according to the invention arepreferably designated according to the process of their synthesis andnot necessarily according to the end product (e.g., a completelyhydrogenated polyisoprene is preferably characterized as a hydrogenatedpolyisoprene homopolymer and preferably not as an alternatingethylene-propylene copolymer).

Examples of natural and synthetic polymers include, but are not limitedto, (co)polymers containing repeat units and/or (co)polymers madeincluding precursors (i.e., monomers, dimers, oligomers, and the like,and combinations thereof) of aliphatic ethers (such as methylene oxide,ethylene oxide, propylene oxide, tetramethylene oxide, and the like, andcopolymers and combinations thereof), aliphatic esters (such ascaprolactones, e.g., e-caprolactone, alkylene esters, e.g., ethyleneadipate, butylene adipate, ethylene succinate, ethylene sebacate,ethylene glutarate, lactides/lactic acids (such as D-, L-, D,L-, and thelike, and copolymers and combinations thereof), glycolides/glycolicacids, and the like, and combinations or copolymers thereof; and thelike; and copolymers and combinations thereof), aromatic esters (such asethylene terephthalate, butylene terephthalate, isophthalates, and thelike, and copolymers and combinations thereof), aliphatic amides (suchas lactams, e.g., propiolactam, caprolactam, laurolactam, and the like,and combinations and copolymers thereof; polyamides, e.g., nylon 6,6,nylon 6,9, nylon, 6,10, nylon 6,12, and the like; and copolymers andcombinations thereof), siloxanes (such as alkyl and/or dialkylsiloxanes, e.g., methylsiloxane, dimethylsiloxane, methylethylsiloxane,and the like, and combinations and copolymers thereof), urethanes and/orurethaneureas having hard segments made from at least diisocyanates(such as methylene diphenylene diisocyanate (MDI), methylenebis(cyclohexane isocyanate) (H₁₂MDI), isophorone diisocyanate (IPDI),phenylene diisocyanate, cyclohexane diisocyanate, toluene diisocyanate(TDI), methylcyclohexane diisocyanate, or the like, or combinationsthereof) in combination with either diols (such as ethylene glycol,propylene glycol, butylene glycol, hexamethylene glycol,dihydroxybenzene, or the like, or a combination thereof) or diamines(such as ethylenediamine, propylenediamine, hexarnethylenediamine,diaminocyclohexane, aniline, or the like, or a combination thereof) orboth, optionally also including trifunctional and/or tetrafunctionalcomponents (such as triisocyanates, tetraisocyanates, triols, tetrols,triamines, tetramines, or the like, or a combination thereof) tochemically crosslink the (co)polymer system, alpha-olefins such aspolyethylene (particularly UHMWPE), at least partially halogenated(particularly fluorinated) repeat units (e.g., vinyl halide, vinylidenehalide, tetrahaloethylene, hexahalopropylene, perhaloalkoxy monomerssuch as those that form the commercial (co)polymer PFA available fromDuPont of Wilmington, Del., perhaloester monomers, and the like, andcombinations and copolymers thereof), ionomers (such as those that formthe commercial (co)polymer SURLYN available from DuPont of Wilmington,Del., and the like), and the like, and combinations or copolymersthereof.

Metals and metal alloys useful as implant surfaces in the presentinvention are preferably non-toxic, preferably biocompatible, and caninclude, but are not limited to, titanium, chromium, manganese, cobalt,nickel, zinc, molybdenum, ruthenium, silver, tin, tantalum, gold, andthe like, and combinations and alloys thereof, optionally withnon-enumerated metals. In one embodiment, the metal or metal alloy cancontain titanium, silver, and/or gold.

Metal-containing compounds useful as implant surfaces in the presentinvention are also preferably non-toxic, preferably biocompatible, andare preferably metal-containing carbides, carbonates, nitrides,nitrites, nitrates, oxides, oxynitrides, hydroxides, phosphides,phoshites, phosphates, sulfides, sulfites, sulfates, or combinationsthereof. The reacted metals can include, but are not limited to, thefollowing metals: beryllium, boron, magnesium, aluminum, calcium,titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper,zinc, strontium, zirconium, molybdenum, ruthenium, tin, barium,tantalum, and the like, and combinations thereof, optionally withnon-enumerated metals. In one embodiment, the reacted metal can includeone or more metals of Group IIA of the periodic table. In anotherembodiment, the reacted metal can include one or more of theaforementioned transition metals.

The kind of implant used in the process according to the invention isnot limited and can take any appropriate form and shape desired forand/or required by the application for which it will ultimately be used.Examples of useful implants, therefore, include, but are not limited to:screws (e.g., bone screws, pedicle screws, or the like); tacks; nails(e.g., intramedullary nails, soft-tissue anchoring nails, or the like);pins (e.g., bone pins, immobilizer pins, or the like); plates (e.g.,bone plates, maxillofacial plates, or the like); rods; clamps; staples;springs; stents; sutures; membranes (e.g., for protecting bones orportions thereof, for protecting osteogenic implant compositions, or thelike); catheters; pacemaker or other electronic device leads; xenograft,heterograft, or allograft portions of bone, soft tissue (e.g., muscle),extracellular matrix (ECM, e.g., collagen), cartilagenous material(e.g., joints such as knee, intervertebral discs, ears, noses, or thelike), or the like, or combinations thereof; compositions of orcontaining artificial bone, demineralized bone matrix, soft tissue(e.g., muscle), ECM (e.g., collagen), cartilagenous material (e.g.,joints such as knee, intervertebral discs, ears, noses, or the like), orthe like, or combinations thereof; and the like; and combinationsthereof. In a preferred embodiment, the useful implant is onecommercially available from Synthes (Paoli, Pa.), Stratec (Davos-Platz,Switzerland), and/or Norian (Cupertino, Calif.).

In one embodiment, the implant does not include a stent or a catheter.In another embodiment, the implant does not include a hip jointprosthesis. In another embodiment, the implant does not include aportion of soft tissue, ECM, demineralized bone matrix, or cartilagenousmaterial, nor artificial soft tissue, ECM, or cartilagenous material. Inanother embodiment, the implant does not include a hardened bone cement.

Optionally but preferably (especially for implants that arenon-polymeric and one or more of non-porous, non-absorbent in water oran organic liquid, and non-swellable in water or an organic liquid), thenon-sterile implant is coated with a layer that is usually polymericand/or that is one or more of porous, absorbent toward water or anorganic liquid, and swellable in water or an organic liquid. Thefunction of this coating, when present, is preferably to improve (incomparison to uncoated implants) the uptake of active agent (which istypically present in a solution of water or an organic liquid) to laterform an active agent-loaded implant.

Exemplary coatings can include, but are not limited to, (co)polymerscontaining repeat units and/or (co)polymers made including precursors(i.e., monomers, dimers, oligomers, and the like, and combinationsthereof) of aliphatic ethers (such as methylene oxide, ethylene oxide,propylene oxide, tetrarnethylene oxide, and the like, and copolymers andcombinations thereof); aliphatic esters (such as caprolactones, e.g.,ε-caprolactone); alkylene esters, e.g., ethylene adipate, butyleneadipate, ethylene succinate, ethylene sebacate, ethylene glutarate,lactides/lactic acids (such as D-, L-, D,L-, and the like, andcopolymers and combinations thereof), glycolides/glycolic acids, and thelike, and combinations or copolymers thereof; and the like; andcopolymers and combinations thereof), aromatic esters (such as ethyleneterephthalate, butylene terephthalate, isophthalates, and the like, andcopolymers and combinations thereof), aliphatic amides (such as lactams,e.g., propiolactam, caprolactam, laurolactam, and the like, andcombinations and copolymers thereof; polyamides, e.g., nylon 6,6, nylon6,9, nylon, 6,10, nylon 6,12, and the like; and copolymers andcombinations thereof), siloxanes (such as alkyl and/or dialkylsiloxanes, e.g., methylsiloxane, dimethylsiloxane, methylethylsiloxane,and the like, and combinations and copolymers thereof), urethanes and/orurethaneureas having hard segments made from at least diisocyanates(such as methylene diphenylene diisocyanate (MDI), methylenebis(cyclohexane isocyanate) (H₁₂MDI), isophorone diisocyanate (IPDI),phenylene diisocyanate, cyclohexane diisocyanate, toluene diisocyanate(TDI), methylcyclohexane diisocyanate, or the like, or combinationsthereof) in combination with either diols (such as ethylene glycol,propylene glycol, butylene glycol, hexamethylene glycol,dihydroxybenzene, or the like, or a combination thereof) or diamines(such as ethylenediamine, propylenediamine, hexamethylenediamine,diaminocyclohexane, aniline, or the like, or a combination thereof) orboth, optionally also including trifunctional and/or tetrafunctionalcomponents (such as triisocyanates, tetraisocyanates, triols, tetrols,triamines, tetramines, or the like, or a combination thereof) tochemically crosslink the (co)polymer system, alpha-olefins such aspolyethylene (particularly UHMWPE), at least partially halogenated(particularly fluorinated) repeat units (e.g., vinyl halide, vinylidenehalide, tetrahaloethylene, hexahalopropylene, perhaloalkoxy monomerssuch as those that form the commercial (co)polymer PFA available fromDuPont of Wilmington, Del., perhaloester monomers, and the like, andcombinations and copolymers thereof), ionomers (such as those that formthe commercial (co)polymer SURLYN available from DuPont of Wilmington,Del., and the like), and the like, and combinations or copolymersthereof. Additionally or alternately, (co)polymers that are naturallyoccurring (or that are synthesized to approximate those that arenaturally occurring) may be useful in the coating layer according to theinvention, e.g., (co)polymers containing and/or made from hyaluronicacid and/or a salt thereof (such as lithium, sodium, potassium,magnesium, calcium, barium, or the like, or a combination thereof),collagen (such as type I, type II or a combination thereof), or thelike, or a combination thereof. In one particular embodiment, thecoating layer contains or consists essentially of hyaluronic acid and/ora salt thereof (such as sodium hyaluronate). In another particularembodiment, the coating layer contains or consists essentially of apolylactic acid homopolymer or copolymer, e.g., poly(D,L-lactide),poly(D-lactic acid-co-L-lactic acid), or a combination thereof.

As is known in the art, the coating layer composition may optionallyadditionally include other conventional additives that may include, butare not limited to, leveling agents, various stabilizers, pH adjustingagents, defoaming agents, co-solvents, and the like, and combinationsthereof, particularly if compatible with the intended use of the coatedimplant.

The nature of the chemical and/or physical properties of the coating canbe matched to the chemical and/or physical properties of the activeagent. Optionally, where the coating surface has vastly differentchemical and/or physical properties than the active agent and/or activeagent solution, a treatment step may be performed after the implant iscoated. When performed, the treatment step includes chemically altering(e.g., functionalizing, at least partially charging, ionizing, exciting,activating, or the like, or a combination thereof) the non-sterileimplant surface to attain a more hydrophilic surface and/or a surfacemore prone to absorb, to adsorb, and/or to retain active agent, e.g.,from solution (depending upon whether the active agent is in an aqueoussolution or in a solution containing an organic solvent).

If necessary to assure proper adhesion and retention of theaforementioned coating layer to the non-sterile implant, an optionaltreatment step may be performed before the implant is coated. Thetreatment step may include chemically (e.g., functionalizing, at leastpartially charging, ionizing, exciting, activating, or the like, or acombination thereof) and/or physically (e.g., leveling, smoothing,roughening, ablating, or the like, or a combination thereof) alteringthe non-sterile implant surface. Additionally or alternately, thetreatment step may include applying pressure to and/or adding waterand/or an organic liquid to the coated layer, e.g., to ensure ascomplete a contact with the implant surface as possible.

If necessary or desired during and/or after the coating step, heatand/or reduced pressure may be applied to cure and/or dry the coatinglayer.

The non-sterile (coated) implant can then be sterilized by anyconvenient sterilization process known to those in the art. Exemplarysterilization processes include, but are not limited to, the applicationof heat (e.g., through increasing temperature and/or through contactwith a heated object such as steam, i.e., autoclaving), irradiation(e.g., with UV light, gamma rays, or the like, or combination thereof),chemicals (e.g., exposure to ethylene oxide), or the like, or somecombination thereof. Once the (coated) implant is sterilized, thesterilized implant may be packaged and/or shipped for later use.

After the coating process is completed, the coated implant can also becleaned, in addition to being sterilized. Due to the absence of anyactive agents on/in the coated implant, a fairly extended shelf-life canbe expected.

Alternately, a pre-packaged, sterile, coated implant (e.g., containingsubstantially no active agents or, if containing any active agent, theactive agent being of a kind and/or in an available concentrationinsufficient for attaining the desired therapeutic goal) may beobtained, e.g., through commercial means and may alternately be used forconvenience, instead of coating a commercially-obtained orpre-manufactured non-sterile implant.

The coating layer can be applied by any of a number of differentprocesses known to those of skill in the art after fabrication of thenon-sterile implant (e.g., by immersion or dip-coating, spray-coating,wipe-coating, injection molding, compression molding, plasma deposition,wet chemical reaction, or the like, or some combination thereof), oreven during fabrication of the non-sterile implant (e.g., by co-molding,co-extrusion, simultaneous (co)polymerization, selective temperatureprofiling, or the like, or a combination thereof). If an appreciableamount of solvent(s) or other undesired volatile compounds is presentduring the coating process (e.g., in spray-coating, or particularly indip-coating and wet chemical reaction, processes), an optional curing,or de-volatilization, step may be undertaken. Heating and/or applying areduced pressure can help speed up de-volatilization of the solvent(s),and/or of any other volatile compounds present, in order to ensureproper setting, viscosity, hardness, and/or the like, in the coatinglayer. In addition, if a porous coating layer is desired,de-volatilization, e.g., by applying a combination of relatively highheat (typically not high enough to cause significant undesirableoxidation or degradation in either the coating layer or the underlyingnon-sterile implant, or both) with a relatively high vacuum (e.g., thecombination of reduced pressure and the increased temperature can allowsufficient volatilization of the solvent(s) and/or of any other volatilecompound(s) present so as to encourage those compounds to boilrelatively rapidly and thus to cause pockets/bubbles of escaping gas toform; by adjusting the viscosity, hardness, and/or (co)polymer fractionin the coating layer, the bubbles can be induced to coalesce to providea certain level of porosity in the coating layer). Although thecombination of relatively high heat with a relatively high vacuum cangenerally result in a highly non-uniform coating layer and/or coatinglayer outer surface, such non-uniformity may be an acceptable effect ofobtaining a porous coating.

It is noted that, in certain cases, it may not be desirable to coat theentire surface of the non-sterile implant. For example, for implantsthat may typically encounter significant and/or repetitive shear and/orfrictional stresses, but typically not those that encounter onlyextensional and/or compressive stresses, such that a coating layer wouldquickly delaminate or be worn away and thus would be of little practicalvalue. Such circumstances may typically arise in, but are in no waylimited to, the context of artificial joints or portions thereof;invertebral spinal discs; artificial muscles or portions thereof;springs; the legs of a staple or the end of a tack, nail, or pin thatare driven into bone; the threading of a screw that is twisted intobone; and the like. In such circumstances, the coating layer mayoptionally be applied only to a selected portion of the implant (e.g.,to the portion of the implant that preferably does not encountersignificant and/or repetitive shear and/or frictional stresses).

The thickness of the coating layer is not necessarily constrained, noris the thickness necessarily uniform on all portions of the implant(which are coated—the uncoated regions of the implant, if any, arespecifically excluded from this uniformity consideration). Indeed, thecoating layer (or the surface layer of the implant itself, if uncoated)is preferably thick enough to allow and/or facilitate physical and/orchemical association between the coating layer and the active agent (orthe active agent-containing solution). Thus, in one embodiment, theaverage thickness of the coating region is from about 10 nm to about 1mm, depending upon the application for which the coated implant is to beused. In embodiments where a relatively thin coating layer is desired,the average thickness can be less than about 1000 nm, alternately fromabout 10 nm to about 1000 nm, from about 20 nm to about 500 nm, fromabout 10 nm to about 250 nm, from about 100 nm to about 1000 nm, or fromabout 250 nm to about 800 nm. In embodiments where a relatively thickcoating layer is desired, the average thickness is from about 1 micronto about 1000 microns, alternately from about 1 micron to about 500microns, from about 2 microns to about 300 microns, from about 5 micronsto about 500 microns, from about 10 microns to about 800 microns, fromabout 50 microns to about 750 microns, or from about 250 microns toabout 900 microns.

By loading the active agent into/onto/within the implant coating, theactive agent can thereby be concentrated where it is most needed invivo, while its presence, and consequently its effect, throughout therest of the body can thus be minimized. An “active agent,” as usedherein, should be understood to mean an agent that exhibits or can becaused to exhibit a therapeutically or diagnostically beneficial effectin the body.

The active agent (while the term “active agent” is referred to in itssingular form, without any intent to limit, it should be understood thatthis term refers equally to mixtures and/or complexes of multiple activeagents, which are also considered to be part of the present invention)may be chemically and/or physically associated with the coating layer(or with the surface of the sterilized implant, if no separately addedcoating layer is desired or necessary) using any number of means knownto those of skill in the art. Indeed, the active agent may be contactedwith the coating layer by means similar to those used to deposit thecoating layer (e.g., immersion or dip-coating, spray-coating,wipe-coating, wet chemical reaction, or the like, or some combinationthereof). While the pure active agent itself is typically a liquid or asolid between about room temperature (let's say about 15° C.) and abouthuman body temperature (about 37° C.), an advantage may be obtained byplacing or obtaining the active agent in an acceptable carrier/solution(hereinafter “solution,” for convenience only and without intent tolimit). The solution need not completely dissolve the active agent(although that may be desired in some embodiments of the presentinvention), but generally should sufficiently attain a viscositysufficient to allow the active agent to physically and/or chemicallyassociate with the coating layer (e.g., in some embodiments, a moreviscous solution may be desired so as to attain a thicker coating suchas in an immersion or dip-coating process; in other embodiments, a lessviscous solution may be desired so as to attain a thinner coating suchas in an immersion or dip-coating process or so as to attain better flowsuch as through the tubes/pipes of a spray-coating apparatus). Thus,precipitated solutions, colloidal solutions, suspensions, emulsions,latices, flocculated solutions, agglomerated solutions, supersaturatedsolutions, and the like can be acceptable substitutes for substantiallyand/or completely dissolved active agent solutions.

There are many potential active agent categories for loading in/on the(coating layer of the) implants according to the present invention.Which category of active agents, and in fact which particular activeagent, to employ will typically depend upon the goal to be attained bythe active agent and optionally but preferably also upon the applicationfor which the implant is to be used. For instance, where the implant isassociated with a bone injury (e.g., bone screw, bone plate, a bonereplacement composition, a protective membrane for bone replacementcomposition, or the like), a useful active agent may include anosseointegrative, osteoconductive, and/or osteoinductive agent (such asa morphogenic protein, a mitogenic protein, or a combination thereof),an antibacterial compound, an angiogenesis agent, an antiinflammatoryagent, a nutrient, or the like, or a combination thereof, optionallydepending upon a particular patient or surgical need. A non-exclusivelist of active agents follows: antibacterials, antivirals,antimicrobials, angiogenesis agents, antiinflammatories, anticanceragents, antiproliferative agents, anticlotting agents, antioxidants,antifungals, analgesics, antiseptics, bioabsorbability/bioresorbabilityenhancers, bisphosphonates, calcitonins, chemotherapeutics, clottingagents, drugs for treating pain, immune system boosters,immunosuppressants, immunomodulators, nutrients (e.g., vitamins),osteoclast inhibitors, osteoconductors, osteoinductors, osseointegrativeagents, statins, vasodilators, vasoconstrictors, salts thereof (whereapplicable), and combinations thereof. Other additionally or alternatelyacceptable active agents and active agent categories can be found, e.g.,in U.S. Pat. No. 6,221,383, the disclosure of which is herebyincorporated by reference.

In a preferred embodiment, the at least one active agent contains orconsists essentially of a bisphosphonate, a monophosphonate (e.g., suchas described in U.S. Pat. No. 6,716,825, the contents of which areincorporated herein by reference), vitamin D and/or a vitamin Dderivative/analog (e.g., such as described in U.S. Pat. Nos. 6,503,893and 6,242,434, the contents of each of which are incorporated herein byreference), calcitonin, a statin, or a combination thereof. In anotherpreferred embodiment, the active agent contains or consists essentiallyof an anti-angiogenesis agent, an anticancer agent, an antiproliferativeagent, an osteoclast inhibitor, a vasodilator, or a combination thereof.As used herein, when used to precede element(s) of the invention, thearticles “a” and “an” should be understood to mean one or more of theelement(s), and not merely a single one of the element(s).

Bisphosphonate compounds useful in the present invention should beunderstood to encompass the acid form of the compounds, as well aspartially- and/or fully-substituted salt and/or ester forms of thecompounds, while alternately or additionally including partially and/orfully hydrated forms of the compounds. Examples of bisphosphonatesaccording to the invention include, but are not limited to, etidronate(e.g., commercially available under the tradename DIDRONEL™),clodronate/clodrinate (e.g., commercially available in its disodium saltform from Leiras Oy under the tradename BONEFOS™), pamidronate (e.g.,commercially available under the tradename AREDIA™), alendronate (e.g.,commercially available in its sodium salt form from Merck under thetradename FOSAMAX™), olpadronate, amino-olpadronate, ibandronate,neridronate, nedrinate, medronate, tiludronate (e.g., commerciallyavailable from Sanofi under the tradename SKELID™), risedronate (e.g.,commercially available from Proctor & Gamble under the tradenameACTONEL™), zolendronate (e.g., commercially available in its acid formunder the tradename ZOMETA™), EB-1053, YM-175, CGP 42′446, YM 529,U-81581, FR-78844, BM-21.0955, those bisphosphonates and/orbisphosphinic acid derivatives described in Published U.S. PatentApplication No. US 2004/0176327 A1, those bisphosphonates and/orbisphosphinic acid derivatives described in U.S. Pat. No. 5,403,829,those bisphosphonates and/or bisphosphinic acid derivatives described inU.S. Pat. No. 6,548,042, those bisphosphonates and/or bisphosphinic acidderivatives described in U.S. Pat. No. 6,750,340, and the like, andcombinations thereof.

In other embodiments, the active agent can include an antibacterialagent, an antiviral agent, an osseointegrative, osteoconductive, and/orosteoinductive agent, or a combination thereof. In another embodiment,the active agent can contain or may consist essentially of mitogenicgrowth factors such as IGF and/or PDGF, morphogenic growth factors suchas TGF and/or BMP, osteoclast inhibitors such as calcitonin and/orbisphosphonates, antiinflammatories, and any combination thereof.

In the embodiment of the coating of the invention having a therapeuticor diagnostic agent bound to the medical device surface, directly or viaa linking agent, the coating of the invention can advantageously providelocalized delivery of the therapeutic or diagnostic agent. Similarly,the coating of the invention can also improve the residence time of thetherapeutic or diagnostic agent. By binding the agent to the device, therapid clearance from the bloodstream of the therapeutic or diagnosticagent, as for example when the body's immune system phagocytizes thetherapeutic agent or a liposome containing the agent, can be avoided.

In one embodiment of the invention, release of the therapeutic ordiagnostic agent within the patient from the medical device surface isprovided by the coating of the invention. Such release of thetherapeutic agent from the device surface may be desirable as occurringover a viable dosage period, e.g., a time release or extended releaseformulation.

In an alternate embodiment, the therapeutic or diagnostic agent caninclude, but is not limited to: proteins; peptides; oligonucleotides;antisense oligonucleotides; cellular adhesion promoting proteins orpeptides including extracellular matrix proteins; polysaccharides suchas heparin, hirudin, hyaluronan, and chondroitin; nitric oxide donatingcompounds; vascular growth factors such as VEGF; antitumor agents suchas Taxol, Paclitaxel, Carboplatin, and Cisplaten; and analogs,derivatives, and mixtures thereof. For example, paclitaxel (taxol)derivatives that may be suitable for use in the present invention caninclude 2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine,2′-glutaryl-taxol, 2′-glutaryl-taxol triethanolamine salt, 2′-O-esterwith N-(dimethylaminoethyl) glutamine, and 2′-O-ester withN-(dimethylaminoethyl) glutamide hydrochloride salt.

Active agent carriers typically have some interaction with the activeagent and can serve to dilute the concentration of the active agent, ifdesired, but generally do not affect the therapeutic and/or diagnosticeffectiveness of the active agent in vivo. However, active agentcarriers may optionally facilitate association of the active agent withthe coated implant surface, e.g., through a physical and/or chemicalassociation both with the active agent and with the coated implantsurface. Carriers, as used herein, include, but are not limited to,adjuvants, excipients, solutions, emulsions, suspensions, colloidalphases, slurries, encapsulants, or the like, or a combination thereof.For example, where an extended dosage time and/or a time releaseformulation is desired, the active agent can be present in a first phasethat is encapsulated by a second phase (e.g., water-in-oil-in-wateremulsions, oil-in-water-in-oil emulsions, microsphere encapsulation,micelle encapsulation, or the like, or a combination thereof.

Examples of active agent carriers can include, but are not limited to,water, saline, buffered aqueous solutions, supercritical carbon dioxide,polar organic solvents, non-polar organic solvents, and the like, andcombinations thereof. In one preferred embodiment, the active agent canbe present in a solution or slurry containing water.

Polar organic solvents include, but are not limited to: alcohols such asethanol, propanol, isopropanol, and the like; alkylene glycols such asethylene glycol, oligomeric poly(ethylene oxide) glycols, butanediol,and the like; multiply hydroxy-functional compounds such as glycerol andthe like; aldehydes such as acetaldehyde, formaldehyde, and the like;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone,and the like; amines such as mono-, di-, and/or tri-substitutedalkylamines; amides such as dimethylformamide, dimethylacetamide,formamide, acetamide, acrylamide, and the like; carboxylicacid-functional compounds such as acetic acid, citric acid, and thelike, as well as salts and/or esters thereof; halogenated hydrocarbonssuch as chloroform, methylene chloride, trichloroethane, bromoform, andthe like, but preferably excluding chlorofluorocarbons andperhalohydrocarbons and optionally excluding halogenated aromaticcompounds; sulfur-containing compounds such as dimethylsulfoxide and thelike; fatty acids such as oleic acid, stearic acid, linoleic acid,behenic acid, palmitin acid, myristic acid, caproic acid, caprylic acid,capric acid, lauric acid, palmitoleic acid, and the like, as well asesters thereof such as diglycerides, triglycerides, and the like;natural or synthetic oils such as corn oil, canola oil, olive oil,sunflower oil, safflower oil, flaxseed oil, grapeseed oil, rapeseed oil,cottonseed oil, linseed oil, sesame oil, peanut oil, and the like;compounds containing more than one type of polar functional groupenumerated herein such as citric acid; and the like; and combinationsthereof.

Non-polar organic solvents include, but are not limited to: straight orbranched alkanes such as pentane, hexanes, decanes, dodecanes, mineralspirits, oligomeric poly(alpha-olefin)s, and the like; cyclic alkanessuch as cyclohexane and the like; straight or branched alkenes such ashexenes, butadiene, hexadiene, octadiene, septatriene, octatriene, andthe like; cyclic alkenes such as cyclohexadiene, cyclooctatriene,norbornene, and the like; and the like; and combinations thereof.

When present with a carrier, the relative concentration of active agentin solution can advantageously be sufficient to permit and/or facilitateadsorption by, absorption into, uptake by, and/or bonding with thecoating layer (and/or the exposed surface layer of the implant). Suchactive agent concentration can be expressed in weight percentage terms(e.g., from about 0.01% to about 75%, from about 0.1% to about 50%, fromabout 0.05% to about 20%, from about 0.2% to about 10%, from about 0.5%to about 25%, from about 0.05% to about 5%, or from about 1% to about40%) or can alternately be expressed in terms of molarity (e.g., fromabout 0.0001 M to about 5 M, from about 0.001 M to about 2 M, from about0.0005 M to about 1 M, from about 0.01 M to about 0.7 M, from about 0.05M to about 1.5 M, from about 0.001 M to about 0.5 M, or from about 0.1 Mto about 3 M), based on the solution/carrier composition, separate fromthe implant.

Any methods known to those of skill in the art for sterilizing solutionscan be utilized in the method according to the present invention. Onepreferred example of sterilizing a solution includes filtering thesolution through an appropriate filter/filtration apparatus (e.g.,containing a filter having pore sizes not larger than about 0.45microns, alternately not larger than about 0.22 microns, which arewidely available commercially through a variety of sources). Thisliquid-based filtration method typically requires that the viscosity ofthe solution be manageable so that the pressure necessary (if any) toallow the solution to pass through the filter and/or requires that theactive agent be sufficiently soluble in the solution so that any activeagent-related solids therein have a diameter no larger than about themaximum pore size of the filter.

In addition, it is noted that the vessel in which the activeagent-containing solution is held must also be sterilized to assure thatthe active agent-containing solution remains sterile throughout themethod according to the invention. Similarly, in a process using anapparatus, each of the components of the apparatus must also besterilized to assure that the active agent-containing solution remainssterile throughout the method according to the invention. Thesesterilization processes can be performed using any of the appropriatesterilization techniques described herein and/or known to those of skillin the art.

The active agent (and its optional carrier) can be handled separately ina vessel, for instance, according to general methods with which doctorsand hospitals are acquainted. Just prior to implantation, the sterilecoated implant can, in one embodiment, be immersed in the vessel inorder to allow the coating layer of the implant to chemically and/orphysically associate with the active agent and/or the active agentsolution.

The active agent loading level (as well as the loading level of thesolvent/carrier, if desired) in/on the implant can be easily andprecisely adjusted by controlling the concentration of the active agent(and optionally the solvent/carrier concentration as well) in thesolution, by carefully choosing the chemical nature of thesolvent/carrier with an eye toward its compatibility or incompatibilitywith the coating layer materiaUsurface, and/or by controlling thecoating layer exposure time thereto.

The active agent loading level in/on the implant (coating layer) canadvantageously be sufficient to permit, facilitate, catalyze, and/orencourage the expression of the desired active agent effect(s) and/orthe attainment of the desired therapeutic/diagnostic result(s) in vivowhen implanted in a subject. Similarly, if the solvent/carrier,independently or in conjunction with the active agent, permits,facilitates, catalyzes, and/or encourages the expression of the desiredactive agent effect(s) and/or the attainment of the desiredtherapeutic/diagnostic result(s) in vivo, then its concentration withinthe implant (coating layer) may be controlled as well.

In one embodiment, where it is desired that two or more active agents beincorporated into/loaded onto the implant, there may be difficulty incombining and/or solublizing the two or more active agents in a singlesolution/carrier composition. In such an embodiment, the two or moreactive agents may be separated into multiple solutions/carriers inmultiple vessels, each vessel containing a solution/carrier compositioncontaining an individual active agent or a soluble/compatiblecombination of active agents. In such an embodiment, the sterile coatedimplant can, e.g., be successively immersed in each of the vessels inorder to allow the coating layer of the implant to chemically and/orphysically associate with the respective active agents and/or the activeagent solutions. In an alternate embodiment, e.g., where the two or moreactive agents cannot effectively be loaded into the same portion of thecoating layer, steps may be taken to load different portions of thecoating layer (whether they be radially uniform and separated by depthfrom the coating layer surface, or whether they be radially distinct andseparated into distinct, e.g., circumferentially-spaced, sectionscontaining the different active agents) with different (sets of) activeagent(s).

Once sufficiently loaded with active agent, the implant can subsequentlybe maneuvered into position within a patient and (optionallypermanently) implanted. In one embodiment, the method according to thepresent invention includes substantially contemporaneously loading thesterile, coated implant with an active agent and implanting the sterile,coated, active agent-loaded implant into a subject. “Substantiallycontemporaneously,” as used herein, should be understood to mean thatthe step of loading the sterile, coated implant with an active agentoccurs at a time from immediately before to a reasonable time beforeimplanting the sterile, coated, active agent-loaded implant into asubject. In one embodiment, the time between forming the activeagent-loaded sterile implant and implanting the active agent-loadedsterile implant into a subject can be from about 20 seconds to about 16hours, alternately from about 1 minute to about 12 hours, from about 20seconds to about 1 hour, from about 30 seconds to about 8 hours, or fromabout 45 seconds to about 3 hours.

The term “at least partially chemically and/or physically associateswith,” which is used herein to describe the interaction of the activeagent (and optionally also the solvent/carrier) with the coating layermaterial and/or surface of the implant, can be defined broadly. Chemicalassociations, which include various levels of hydrogen-bonding, canrange throughout the spectrum from relatively strong associations (e.g.,chemical bonds and ionic charge-related attractions/repulsions) torelatively weak associations (e.g., intermolecular interaction based onpartial electronic charge distributions, or mild polarity, and secondaryintramolecular electronic structure interactions such as alignment ofp-orbitals or empty d- or f-orbitals that can lead to intermolecularcomplexes). Physical associations can also range from relatively strongassociations (e.g., co-crystallinity or co-crystallization,entanglements between relatively high molecular weight materials, andhigh levels of co-alignment or co-orientation) to relatively weakassociations (e.g., low levels of co-alignment or co-orientation, vander Waals forces, and alteration of β-, γ-, and/or δ- phase transitionslike a glass-amorphous liquid transition in polymers/oligomers such asthrough plasticization or the like). While certain types of relativelystrong interactions between the implant (coating layer) and the activeagent and/or active agent solution can be undesirable in circumstanceswhere immediate or relatively quick active agent release in vivo isdesired, such strong interactions may be desirable in othercircumstances such as where relatively slow or extended/time release invivo is desired. Thus, the desired release characteristics, as well asthe uptake/loading characteristics, of the active agent (and/orsolution/carrier) can be controlled by controlling the strength orweakness of the interactions within the system.

Another aspect of the invention relates to the sterile, coated, activeagent-loaded implant formed according to the method of the inventiondescribed above.

Another aspect of the invention relates to a kit containing (1) asterile, coated implant formed according to the method of the inventiondescribed above and (2) at least one sterile solution/carrier, eachcontaining at least one active agent according to the invention.

In one embodiment of this aspect of the invention, where two or moreactive agents may be difficult to combine and/or solublize in a singlesolution/carrier composition, they may be separated into multiplesolutions/carriers, such that each solution/carrier composition cancontain an individual active agent or a soluble/compatible combinationof active agents.

In a preferred embodiment, the kit includes a single solution/carriercontaining a solublized/compatible combination of one or moresolvents/carriers and the at least one active agent according to theinvention.

Another aspect of the present invention relates to a method for in situtreatment of malignant cells from a cancer associated with boneinvolving: a) treatment of a primary cancer associated with bone, andincluding positioning an implant according to the invention (i.e.,containing and/or coated with an active agent) for treating themalignant cells directly in/on a site containing the malignant cells;and/or b) treatment of a primary cancer associated with bone, andincluding positioning an implant according to the invention (i.e.,containing and/or coated with an active agent) for treating themalignant cells indirectly among/near (e.g., by placing the implant inan area immediately proximal to) a site containing the malignant cells.

As used herein, a cancer that is, or malignant cells that are,“associated with bone” should be understood to includecancers/malignancies of the skeletal system (i.e., bone, marrow, jointand/or vertebral cartilage, cartilagenous fluids, teeth,undifferentiated and/or partially differentiated cells that candifferentiate into the preceding, and any combination thereof). In onepreferred embodiment, the cancer is or encompasses a bone cancer.

Anon-exclusive list of cancers associated with bone include, but are notlimited to, osteosarcoma, osteoblastoma, myeloma, multiple myeloma,osteomyeloma, or the like, or a combination thereof. For example, anon-exclusive list of cells that may be malignant and for whichtreatment according to the invention is warranted includes, but is notlimited to, osteoblasts, osteoclasts, cells of the bone corticum, stemcells, marrow cells, cartilage cells, or the like, or a combinationthereof.

Another aspect of the present invention relates to a method for in situtreatment of malignant cells from a cancer associated with boneincluding: a) positioning an implant according to the invention (i.e.,containing and/or coated with an active agent) for treating themalignant cells direcdyin/no a surgical site from which the malignantcells were previously removed/excised; and/or b) positioning an implantaccording to the invention (i.e., containing and/or coated with anactive agent) for treating the malignant cells indirectly among/near(e.g., by placing the implant in an area immediately proximal to) asurgical site from which the malignant cells were previouslyremoved/excised.

In one embodiment according to this aspect of the invention, the implantdoes not include a hardened bone cement within the bulk of which the atleast one active agent is contained. In this embodiment, however, theimplant may contain a bone cement, which contains substantially noactive agents within its bulk, but which possesses a coating layercontaining the at least one active agent. As used herein in reference toone or more compounds, the phrase “contains substantially no” means thatthere is present not more than about 0.5% by weight, preferably not morethan about 0.1% by weight, for example not more than about 0.01% byweight, of the one or more compounds. Additionally or alternately, thephrase “contains substantially no,” in reference to one or morecompounds, means that there is present an amount of the one or morecompounds less than that necessary to have the desired therapeuticeffect (e.g., reducing, inhibiting, ha)ting, or reversing the growth ofcancer/malignant cells associated with bone), either in vivo or invitro.

In another embodiment according to this aspect of the invention, the atleast one active agent includes a combination of vitamin D (and/or avitamin D derivative/analog) and a bisphosphonate. However, in analternate embodiment of the latter method, where the malignant cells arenot a result of a primary bone cancer but are instead a result of ametastatic cancer that has spread to bone, the at least one active agentdoes not include a combination of vitamin D (and/or a vitamin Dderivative/analog) and a bisphosphonate.

As used herein, a cancer that is, or malignant cells that are,“associated with bone” should be understood to includecancers/malignancies of the skeletal system (i.e., bone, marrow, jointand/or vertebral cartilage, cartilagenous fluids, teeth,undifferentiated and/or partially differentiated cells that candifferentiate into the preceding, and any combination thereof). In onepreferred embodiment, the cancer is or encompasses a bone cancer.

A non-exclusive list of cancers associated with bone include, but arenot limited to, osteosarcoma, osteoblastoma, myeloma, multiple myeloma,osteomyeloma, or the like, or a combination thereof. For example, anon-exclusive list of cells that may be malignant and for whichtreatment according to the invention is warranted includes, but is notlimited to, osteoblasts, osteoclasts, cells of the bone corticum, stemcells, marrow cells, cartilage cells, or the like, or a combinationthereof.

While one or more particular forms of the invention have beenillustrated and described, it will also be apparent to those skilled inthe art that various modifications can be made without departing fromthe spirit and scope of the invention.

Each reference cited or referenced herein is hereby incorporated byreference in its entirety herein.

1. A method for in situ treatment of malignant cells from a cancerassociated with bone, which comprises positioning among the malignantcells an implant that at least partially chemically and/or physicallyassociates with at least one active agent for treating the malignantcells, wherein the cancer associated with bone is a primary cancer. 2.The method of claim 1, wherein the positioning of the implant occurssuch that the implant is directly within a site including the malignantcells.
 3. The method of claim 1, wherein the positioning of the implantoccurs such that the implant is directly on a site including themalignant cells.
 4. The method of claim 1, wherein the positioning ofthe implant occurs such that the implant is in an area immediatelyproximal to a site including the malignant cells.
 5. The method of claim1, wherein the implant comprises a screw; a tack; a nail; a pin; aplate; a rod; a clamp; a staple; a spring; a stent; a suture; amembrane; a catheter; a pacemaker or other electronic device lead; or acombination thereof.
 6. The method of claim 5, wherein the implantpossesses a coating layer comprising a (co)polymer containing repeatunits, and/or a (co)polymer made including precursors, of: aliphaticethers; aliphatic esters; aromatic esters; aliphatic amides; polyamides;siloxanes; urethanes, urethaneureas, or both, having hard segments madefrom multifunctional isocyanates in combination with multifunctionalhydroxy compounds, multifunctional amines, or both; alpha-olefins; atleast partially halogenated repeat units; ionomers; hyaluronic acidand/or a salt thereof; collagen; and combinations, copolymers, orreaction products thereof.
 7. The method of claim 1, wherein the primarycancer comprises a primary bone cancer.
 8. The method of claim 1,wherein the at least one active agent comprises a bisphosphonate, amonophosphonate, vitamin D and/or a vitamin D derivative, calcitonin, astatin, or a combination thereof.
 9. The method of claim 1, wherein theat least one active agent comprises an anti-angiogenesis agent, ananticancer agent, an antiproliferative agent, an osteoclast inhibitor, avasodilator, or a combination thereof.
 10. The method of claim 1,wherein the implant comprises a xenograft, heterograft, or allograftportion of bone, soft tissue, extracellular matrix, cartilagenousmaterial, or a combination thereof; a composition of or containingartificial bone, demineralized bone matrix, soft tissue, extracellularmatrix, cartilagenous material, or a combination thereof; a bone cement;or a combination thereof.
 11. The method of claim 10, wherein theimplant possesses a coating layer comprising a (co)polymer containingrepeat units, and/or a (co)polymer made including precursors, of:aliphatic ethers; aliphatic esters; aromatic esters; aliphatic amides;polyamides; siloxanes; urethanes, urethaneureas, or both, having hardsegments made from multifunctional isocyanates in combination withmultifunctional hydroxy compounds, multifunctional amines, or both;alpha-olefins; at least partially halogenated repeat units; ionomers;hyaluronic acid and/or a salt thereof; collagen; and combinations,copolymers, or reaction products thereof.
 12. The method of claim 1,wherein the at least one active agent comprises: a bisphosphonateselected from the group consisting of etidronate, clodronate,pamidronate, alendronate, olpadronate, amino-olpadronate, ibandronate,neridronate, nedrinate, medronate, tiludronate, risedronate,zolendronate, EA-1053, YM-175, CGP 42′446, YM 529, U-81581, FR-78844,BM-21.0955, and a combination thereof; vitamin D, a vitamin Dderivative, a combination of vitamin D and a vitamin D derivative; andcombinations of any of the preceding agents.
 13. A method for in situtreatment of malignant cells from a cancer associated with bone, whichcomprises positioning among the malignant cells an implant that at leastpartially chemically and/or physically associates with at least oneactive agent for treating the malignant cells, with the proviso that theimplant does not comprise a hardened bone cement within the bulk ofwhich the at least one active agent is contained.
 14. The method ofclaim 13, wherein the positioning of the implant occurs such that theimplant is directly within a site including the malignant cells.
 15. Themethod of claim 13, wherein the positioning of the implant occurs suchthat the implant is directly on a site including the malignant cells.16. The method of claim 13, wherein the positioning of the implantoccurs such that the mplant is in an area immediately proximal to a siteincluding the malignant cells.
 17. The method of claim 13, wherein theimplant comprises a screw; a tack; a nail; a pin; a plate; a rod; aclamp; a staple; a spring; a stent; a suture; a membrane; a catheter; apacemaker or other electronic device lead; or a combination thereof. 18.The method of claim 17, wherein the implant possesses a coating layercomprising a (co)polymer containing repeat units, and/or a (co)polymermade including precursors, of: aliphatic ethers; aliphatic esters;alkylene esters; aromatic esters ; aliphatic amides; polyamides;siloxanes; urethanes, urethaneureas, or both, having hard segments madefrom multifunctional isocyanates in combination with multifunctionalhydroxy compounds, multifunctional amines, or both; alpha-olefins; atleast partially halogenated repeat units; ionomers; hyaluronic acidand/or a salt thereof; collagen; and combinations, copolymers, orreaction products thereof.
 19. The method of claim 13, wherein thecancer associated with bone is a primary cancer.
 20. The method of claim19, wherein the primary cancer comprises a primary bone cancer.
 21. Themethod of claim 13, wherein the at least one active agent comprises abisphosphonate, a monophosphonate, vitamin D and/or a vitamin Dderivative, calcitonin, a statin, or a combination thereof.
 22. Themethod of claim 13, wherein the at least one active agent comprises ananti-angiogenesis agent, an anticancer agent, an antiproliferativeagent, an osteoclast inhibitor, a vasodilator, or a combination thereof.23. The method of claim 13, wherein the implant comprises a xenograft,heterograft, or allograft portion of bone, soft tissue, extracellularmatrix, cartilagenous material, or a combination thereof; a compositionof or containing artificial bone, demineralized bone matrix, softtissue, extracellular matrix, cartilagenous material, or a combinationthereof; a bone cement; or a combination thereof.
 24. The method ofclaim 23, wherein the implant possesses a coating layer comprising a(co)polymer containing repeat units, and/or a (co)polymer made includingprecursors, of: aliphatic ethers; aliphatic esters; alkylene esters;aromatic esters ; aliphatic amides; polyamides; siloxanes; urethanes,urethaneureas, or both, having hard segments made from multifunctionalisocyanates in combination with multifunctional hydroxy compounds,multifunctional amines, or both; alpha-olefins; at least partiallyhalogenated repeat units; ionomers; hyaluronic acid and/or a saltthereof; collagen; and combinations, copolymers, or reaction productsthereof.
 25. The method of claim 13, wherein the at least one activeagent comprises: a bisphosphonate selected from the group consisting ofetidronate, clodronate, pamidronate, alendronate, olpadronate,amino-olpadronate, ibandronate, neridronate, nedrinate, medronate,tiludronate, risedronate, zolendronate, EB-1053, YM-175, CGP 42′446, YM529, U-81581, FR-78844, BM-21.0955, and a combination thereof; vitaminD, a vitamin D derivative, a combination of vitamin D and a vitamin Dderivative; and combinations of any of the preceding agents.
 26. Amedical device for in situ treatment of malignant cells from a cancerassociated with bone, which comprises: a sterile, coated implantselected from the group consisting of a screw; a tack; a nail; a pin; aplate; a rod; a clamp; a staple; a spring; a stent; a suture; amembrane; a catheter; a pacemaker or other electronic device lead; axenograft, heterograft, or allograft portion of bone, soft tissue,extracellular matrix, cartilagenous material, or a combination thereof;a composition of or containing artificial bone, demineralized bonematrix, soft tissue, extracellular matrix, cartilagenous material, or acombination thereof; a bone cement; or a combination thereof, whereinthe implant possesses a coating layer comprising a (co)polymer thatcomprises: aliphatic ethers; aliphatic esters; alkylene esters; aromaticesters; aliphatic amides; polyamides; siloxanes; urethanes,urethaneureas, or both, having hard segments made from multifunctionalisocyanates in combination with multifunctional hydroxy compounds,multifunctional amines, or both; alpha-olefins; at least partiallyhalogenated repeat units; ionomers; hyaluronic acid and/or a saltthereof; collagen; and combinations, copolymers, or reaction productsthereof, and wherein the implant at least partially chemically and/orphysically associates with at least one active agent selected from thegroup consisting of a bisphosphonate, a monophosphonate, vitamin Dand/or a vitamin D derivative, calcitonin, a statin, ananti-angiogenesis agent, an anticancer agent, an antiproliferativeagent, an osteoclast inhibitor, a vasodilator, and a combinationthereof.
 27. A kit for in situ treatment of malignant cells from acancer associated with bone, which comprises: (1) a sterile, coatedimplant selected from the group consisting of a screw; a tack; a nail; apin; a plate; a rod; a clamp; a staple; a spring; a stent; a suture; amembrane; a catheter; a pacemaker or other electronic device lead; axenograft, heterograft, or allograft portion of bone, soft tissue,extracellular matrix, cartilagenous material, or a combination thereof;a composition of or containing artificial bone, demineralized bonematrix, soft tissue, extracellular matrix, cartilagenous material, or acombination thereof; a bone cement; and a combination thereof, whereinthe implant possesses a coating layer comprising a (co)polymer thatcomprises: aliphatic ethers; aliphatic esters; alkylene esters; aromaticesters; aliphatic amides; polyamides; siloxanes; urethanes,urethaneureas, or both, having hard segments made from multifunctionalisocyanates in combination with multifunctional hydroxy compounds,multifunctional amines, or both; alpha-olefins; at least partiallyhalogenated repeat units; ionomers; hyaluronic acid and/or a saltthereof; collagen; and combinations, copolymers, or reaction productsthereof; and (2) one or more sterile solutions, carriers, or both, eachsolution, carrier, or combination thereof comprising at least one activeagent selected from the group consisting of a bisphosphonate, amonophosphonate, vitamin D and/or a vitamin D derivative, calcitonin, astatin, an anti-angiogenesis agent, an anticancer agent, anantiproliferative agent, an osteoclast inhibitor, a vasodilator, and acombination thereof.